Bacterial biofilms exist in natural, medical, and engineering environments. The biofilm may offer a selective advantage to a microorganism to ensure its survival, or allow it a certain amount of time to exist in a dormant state until suitable growth conditions arise. This selective advantage could pose serious threats to human health. For example, biofilms are involved in 65% of human bacterial infections. Biofilms are also involved in prostatitis, biliary tract infections, urinary tract infections, cystitis, pyelonephritis, lung infections, sinus infections, ear infections, acne, and chronic wounds.
Biofilms contribute to a variety of medical conditions. Each year in the United States alone, over 7 million patients receive medical device implants, including central venous catheters, endotracheal tubes, mechanical heart valves, pacemakers, and prosthetic joints. Approximately one-half of these patients develop nosocomial infections, and approximately 80,000 deaths per year are attributed to nosocomial infections. Biofilms provide a structural matrix that facilitates bacterial adhesion to the inert surfaces of medical device implants and venous catheters. Microscopic studies confirm that central venous catheters are coated by bacteria embedded in biofilms. Unfortunately, more than 1 million patients develop urinary tract infections from such catheters.
Some diseased tissues, such as tumors, are susceptible to bacterial colonization. Bacterial colonization has been identified in calcified human aneurysms, carotid plaques, femoral arterial plaques, and cardiac valves. Arterial calcification resembles infectious lesion formation in animal models of atherosclerosis. A toxin produced by Cag-A positive Helicobacter pylori colonization of the stomach could lead to tissue inflammation and lesions in the arterial walls resulting in atherosclerosis. Bacterial colonization could also lead to the formation of kidney stones. Eradication of bacteria, and the biofilms that protect them, from the diseased tissue enables the host's immune system and/or a pharmaceutical agent to reach the diseased tissue. For example, clostridia spores and attenuated Salmonella typhimurium, used to deliver therapeutic proteins to tumors, may be more effective if the biofilm did not exist or is removed.
Biofilms may also cause diseases, such as cystic fibrosis, or contribute to chronic symptoms. Chronic bacterial infections represent a serious medical problem in the United States. Antibiotics are typically used to treat both acute and chronic infections. In chronic bacterial infections, biofilms protect the bacteria from the antibiotics and the host's immune system, thus increasing the rates of recurring symptoms and resistance to the antibiotics. Researchers theorized that a biofilm gives bacteria a selective advantage by reducing the penetration of an antibiotic to the extent necessary to eradicate the bacteria. Through biofilms, the microbes can resist antibiotics at high concentrations, about 1 to 1.5 thousand times higher than necessary in the absence of biofilms. Not surprisingly, during an infection, bacteria surrounded by biofilms are rarely resolved by the host's immune defense mechanisms.
As discussed above, biofilms provide a protective barrier for bacteria, thus, allowing the bacteria to resist antibiotic treatments. Developers of antibiotics must face the continuous challenge of antibiotic resistance. Antibiotic resistance significantly hinders treatment of the medical condition. For example, microbial resistance to minocycline and rifampin, which are widely used to treat infections, is emerging. A 1998 study of an intensive care unit revealed that 6 out of 7 vancomycin-resistant enterococci were resistant to rifampin.
Biofilm inhibition offers numerous advantages. Bacteria have no known resistance to biofilm inhibitors. Thus, unlike antibiotics, biofilm inhibitors can be used repeatedly and effectively in the same patient and for the same medical condition. For example, biofilm inhibitors may be employed to treat, cure, or prevent acute or chronic infections. They may be used to control microorganisms residing on living tissues. They may also be used to cure, treat, or prevent arterial damage, gastritis, urinary tract infections, cystitis, otitis media, leprosy, tuberculosis, benign prostatic hyperplasia, chronic prostatitis, chronic infections of humans with cystic fibrosis, osteomyelitis, bloodstream infections, skin infections, open wound infections, and any acute or chronic infection that involves or possesses a biofilm.
Biofilm inhibitors can act specifically on the biological mechanisms that provide bacteria protection from antibiotics and from a host's immune system. In one study of urinary catheters, rifampin was able to clear planktonic or suspended methicillin-resistant Staphylococcus aureus, but was unable to eradicate the bacteria in a biofilm. Current treatment of infections, e.g. nosocomial infections, often requires sequential or simultaneous administration of a combination of products, such as amoxicillin/clavulanate and quinupristin/dalfopristin. A direct inhibition of the bacterial mechanisms used to form biofilms may help reduce blood stream infections (BSI).
In addition, a direct inhibition of the bacterial mechanisms used to form biofilms delays the onset of microbial resistance to antibiotics, and possibly, reduces the emergence of multi-resistant bacteria. Another approach to reducing or inhibiting biofilm formation is to apply evolutionary pressure to the bacterial growth mechanisms. Accordingly, extensive research are devoted to elucidating the genes, especially the critical players, that are involved in controlling biofilm formation.
Accordingly, for the reasons discussed above and others, there continues to be a need for a means to control biofilm and its formation.